Urticaria and angioedema

Dr. S. Shanmathi
Senior Resident
Department of Dermatology
 CONTENTS
 Introduction
 Pathogenesis
 Classification
 Clinical Features
 Differential diagnosis
 Investigations
 Provocative test
 Treatment
 MCQs
 Photo quiz
 Introduction

 Urticaria is derived from Latin word

“Urtica” meaning stinging nettle.
 It is a cutaneous reaction pattern
consisting of transient, dermal
swellings in form of wheals or
angioedema.
Wheal  Individual wheals are pruritic ,
pink or pale swellings of
superficial dermis that have red
flare around them and usually
subside within 24 hours.
 In angioedema, the swelling is
 Deeper
 Less well defined
 Painful rather than itchy
 Less erythematous
 Involves deeper tissues such as
hypodermis and submucosa
and
 Takes longer than 24 hours to
 Pathogenesis
 For urticaria / angioedema to happen, vasodilatation and
plasma leakage is required.
 Most commonly, this is brought about by histamine (usually
released by mast cells).
 But many other chemicals like sorbic acid, benzoic acid and
bradykinin can also cause it (not released by mast cells).
 Thus urticaria can be

IgE Dependent
Mast cell dependent

Non IgE Dependent

or

Mast cell independent

Mast cell dependent is more common
Ig E +Allergen Mast cell Degranulation
Non immunological activation or
IgE independent acivation

 In some instances, mast cells are directly activated

by molecules such as
 Substance P
 Morphine
 Codeine
 Complement 5a
 Mediators released by human dermal mast cell
degranulation
Preformed mediators New synthesis of mediators
 Histamine  Prostaglandin D2

 Heparin  Leukotrienes C4, D4, E4

 Platelet activating factor
 Proteases like tryptase
 Mast cell independent urticaria
 Vasoactive stimuli (sorbic acid etc)
 Bradykinin mediated
 C1 inhibitor deficiency
 Hereditary
 Acquired
 ACE inhibitor induced urticaria
 Allergens and Substance P, morphine, Sorbic acid, benzoic
autoantibodies against codeine, complement acid, food additives and
IgE (immunological) 5a (non-immunological) bradykinin (HAE)

Mast cell dependent Mast cell independent

Histamine and
leukotrienes

Vasodilation and
increased permeability

Wheal, angioedema
 Histamine

Blood Nerve
vessels endings

Axon
Erythema Edema Pruritus reflex and
flare

Lewis triple response – erythema, flare and wheal.

Classification and causes of urticaria
Acute urticaria Chronic urticaria
Duration less than 6 Daily or almost daily for more
weeks. than 6 weeks.

 Infections (40%)  Chronic spontaneous urticaria

 Drugs(9%) (autoimmune, pseudoallergic,
 Food items (1%) infection and idiopathic) (65%)
 Idiopathic (50%)  Physical/ inducible urticaria
(35%)
 Urticarial vasculitis (5%)
 Classification of angioedema
Angioedema with wheals Angioedema without wheals
 Associated with urticaria  Hereditary angioedema
 ACE inhibitor associated
angioedema

Urticaria rarely progresses to anaphylaxis, but it

is often a feature of anaphylaxis.
50% of chronic urticaria patients have angioedema.
 Causes
 Exogenous (Allergens and
Pseudoallergens)
 Inhalants : pollens, house dust,
fungi, dander.
 Ingestants : fish, egg, brinjal ,
soy, milk, chocolate, nuts,
(pseudoallergens - food additives,
dyes, preservatives, flavors).

 Drugs : NSAIDs, Polymyxin,

Vancomycin, Morphine, codeine,
Drug induced urticaria
Penicillins, Cephalosporins
 Food likely to cause urticaria
Acute urticaria Chronic urticaria
 Nuts, fish, chocolates, spices  Food additives such as sodium
 Act through type I benzoate, salicylates
hypersensitivity (IgE mediated)  Act by pseudoallergic
mechanism, direct mast cell
activators.
Endogenous
 Infections :
 Gastrointestinal, respiratory, urinary tract infections
 Bacterial, protozoal, helminthic, viral (CMV, EBV, HSV)
 Systemic diseases :
 Hashimoto’s thyroiditis
 Systemic lupus erythematosus
 Chronic active hepatitis
 Malignancies
 Physical urticaria
Urticaria factitia / dermographism Eliciting factor : mechanical
(most common type, red, itchy, linear sheering forces (weals arising
wheal appearing immediately after light within 1-5 minutes, fade in 30
stroking of the skin) min)
Cold contact urticaria Eliciting factor : cold objects,
air, fluids, wind
Heat contact urticaria Eliciting factor : localized heat
Eliciting factor : UV and / or
Solar urticaria
visible light.
Delayed pressure urticaria
Eliciting factor : vertical
(appear at site of pressure on the skin ,
pressure (weals arising with 3 -
painful rather than itchy
12 hrs. latency)
last for more than 24 hrs, poor prognosis)
 Physical urticaria
Eliciting factor : vibratory
Vibratory urticaria / angioedema
forces
Aquagenic urticaria Eliciting factor : water

Cholinergic urticaria Eliciting factor : increase in

(small (2-4mm) erythematous papules core body temperature and
surrounded by a pink flare, most sweating, by exercise or spicy
commonly on trunk and proximal limbs) food.

Contact urticaria
Eliciting factor : contact with
[Can be IgE dependent or independent
urticariogenic substance
(immunologic or non-immunologic)]
Eliciting factor : physical
Exercise induced urticaria / anaphylaxis
exercise
Dermographism
Delayed pressure urticaria
Vibratory angioedema
Heat and cold contact urticaria
Allergic contact urticaria
Cholinergic urticaria
Solar urticaria
 Clinical features and differentials
 Symptoms :
 Pruritus
 Signs :
 Pale pink well defined swellings (Hives or wheals) Spreads
with scratching and coalesce to form large lesions.
 Course of Lesions :
 Lesions last 90 minutes to 24 hours
 Differential diagnoses
 Important to differentiate urticaria from urticarial
dermatoses which are :
 Urticarial vasculitis
 Eosinophilic cellulitis
 Bullous pemphigoid
 Urticarial drug eruptions

 These last more than 24 hours (may be days)

Difference between urticaria and urticarial vasculitis

Urticaria Urticarial vasculitis

 Generalized body involvement  Trunk and proximal limbs
 Individual lesions last less than 24 hours  Individual lesion last more than 24
 Itchy hours
 Don’t leave post inflammatory  Associated with burning and pain
pigmentation  Have purpuric centre and leave post
 Rare systemic symptoms inflammatory pigmentation
 Biopsy does not reveal vasculitis  Systemic symptoms, fever, arthralgia
present
Insect bite allergy or papular urticaria
Erythema multiforme
Urticarial phase of bullous pemphigoid
Larva currens
Cutaneous larva migrans
Urticarial vasculitis
Urticarial vasculitis
Urticaria pigmentosa
Guttate psoriasis
Pityriasis rosea
 Differential diagnosis (contd..)
 Anaphylaxis has urticaria has one of the component, but it
has several other components like bronchoconstriction,
hypotension and flushing.
 Normal / ordinary urticaria almost never progresses to
anaphylaxis.
 Familial cold auto-inflammatory syndromes and paraneoplastic
syndromes also present with urticarial lesions, e.g. Muckle-
Wells syndrome, Schnitzler syndrome.
 But these lesions are non itchy and are associated with
systemic symptoms, and usually arise in infancy /
 Chronic urticaria
 Chronic urticaria can be physical urticaria or spontaneous
urticaria. Depending upon duration of wheals, some inference
can be drawn regarding etiology;
 <1 hour – physical urticaria
 <2 hours – contact urticaria
 1-24 hours – spontaneous urticaria and delayed pressure
urticaria
 >24 hours – urticarial vasculitis
 Associations of chronic urticaria
 Thyroid disease
 Atopic disorders
 Vitiligo
 Pernicious anemia
 Rheumatoid arthritis
 Workup in a patient of urticaria
Careful History
 Travel and work history
 Ingestion of foods, medications, herbals, vitamins
 Recent infection
 Known allergies / atopy
 Family History of allergy or thyroid disease
 Investigations
 Hb, TLC/DLC  Liver Function Tests
 Urine analysis  TSH / anti TPO

 Stool analysis  ANA

 IgE levels
 ESR
 Autologous serum /plasma
 Skin biopsy if lesion present
skin test
>24 hrs, consider urticarial
vasculitis
 Provocation tests for physical urticaria

Dermographism Stroking of skin by blunt object

Delayed pressure urticaria Locally applied weight for 20 min.

Cold urticaria Cold contact (ice cube for 20 min.)

Cholinergic urticaria Physical exercise/hot bath

Contact with water of any
Aquagenic urticaria
temperature
Supervised exercise (shortly after
Exercise anaphylaxis
meal)
Solar urticaria Phototesting
Dermatographism
 Hereditary angioedema
 Recurrent laryngeal edema or colicky abdominal pain, skin
swellings especially on distal limbs.
 May be preceded by reticular erythema.
 Family history present (autosomal dominant).
 Trauma and estrogens are triggers.
 These individuals lack C1 esterase inhibitor (type I) or have
dysduntional form(type II) and over-activity of C1 results in
generation of kallikrein, which converts kininogen to bradykinin.
 Bradykinin acts on vasculature and results in angioedema
attacks.
 Attacks can be life threatening and are associated with arthralgia
too.
 Diagnosis of hereditary angioedema
 Detection of low serum level of C4 is very
sensitive, but non specific screening test.
 Low C1, C2
 Acquired angioedema due to lymphomas and SLE
etc. has low C1q levels along with low C4 levels.

 Rx: Hydrocortisone , Epinephrine , Avil

Differential diagnosis of
angioedema
Facial cellulitis
Orbital cellulitis
Dermatomyositis
Contact dermatitis
Racoon eyes /ecchymosis
 Treatment
 General
 Rule out Anaphylaxis
 Discontinue offending drugs, food, or behavior
 Offer Reassurance

Discuss idiopathic nature of chronic urticaria and

possibility of inability to identify a specific cause.
 European academy of allergy and clinical immunology)
guidelines (EAACI )

 First use second generation antihistamines in baseline

dose.
 Second step in non responsive patients is to increase the
dose by four folds.
 Third step in antihistamine refractory patients is to use
omalizumab, cyclosporine and addition of
monteleukast.
 Fourth step is Dapsone, Colchicine, HCQs, Ranitidine,
Modern second generation H1
antihistamines in standard
dosages
1-2 weeks

Four fold increased dosages

of same antihistamines

2-4 weeks
Add omalizumab,
cyclosporine, monteleukast,
first generation
antihistamines at bed time

Dapsone, colchicine, HCQS, ranitidine, methotrexate,

azathioprine, phototherapy, plasmapheresis etc
 Antihistamines
 Second generation H1 antihistamines are the cornerstone
of treatment for urticaria.

Commonly used drugs are (Baseline Dose)

 Cetirizine (10mg/day)
 Levocetirizine (5 mg/day)
 Fexofenadine (180mg/day)
 Loratidine (10mg/day)
 Desloratidine (5mg/day)
 Antihistamines
 H2 antihistamines
 Ranitidine, 150 mg twice daily
 Famotidine, 20 mg twice daily/40 mg
once daily
 Cimetidine, 400 mg twice daily-obsolete

 Leukotriene-receptor antagonist
 Montelukast, 10 mg once daily
 Zafirlukast, 20 mg twice daily
 Oral steroids
 Oral corticosteroids (short courses for 10
days) are useful in
 Acute severe exacerbations of chronic urticaria
 Severe angioedema
 Delayed pressure urticaria
 Urticarial vasculitis
 Omalizumab

 Omalizumab is humanized monoclonal antibody

against IgE
 approved by US-FDA in 2014 for the treatment of
patients 12 years of age and older with Chronic
urticaria that is not controlled with H1
antihistamine therapy.
 Dose recommended is 300 mg monthly given
subcutaneously.
 Therapy for physical urticaria
Symptomatic dermographism H1 receptor antagonists

Systemic corticosteroids, NSAIDs,

Delayed pressure urticaria sulfasalazine, dapsone,
monteleukast

Cholinergic urticaria H1 receptor antagonists, danazol

H1 receptor antagonists, ketotifen,
Cold urticaria cyproheptadine, Systemic
corticosteroids, epinephrine

Induction of tolerance by UVB/PUVA,

Solar urticaria
sunscreens, hydroxychloroquine

J Allergy Clin Immunol 2014; 2:73-88.

 Three months of good control is
recommended prior to tapering therapies,
and it can be longer for patients with one
or more of the following characteristics :
 Symptoms that were present for years.
 Very severe and difficult to control
symptoms.
 Concomitant physical urticaria.
 Therapy for hereditary angioedema
 Danazol/stanazol for maintenance therapy
 For acute attacks, fresh frozen plasma is the treatment of
choice.
 New drugs available :
 Berinert (nano-filtered C1 concentrate)
 Ruconest (recombinant C1 inhibitor)
 Icatibant (bradykinin B2 receptor antagonist)
 Ecallantide (kallikrein inhibitor)
 Antifibrinolytic : Aminocaproic acid, Tranexamic acid
 MCQ’s

Q.1) What is the screening test of choice for Hereditary angioedema?

A. High C3 levels
B. High C4 levels
C. High C1 levels
D. Low C4 levels
 MCQ’s
Q.2) Chronic urticaria is defined as duration of disease more than :
A. 2 weeks
B. 4weeks
C. 6 weeks
D. 8 weeks

Q.3) What percentage of chronic urticaria have associated angioedema?

E. 20%
F. 30%
G. 50%
H. all
 MCQ’s
Q.4) Pseudo-allergens are
A. Soy
B. Cheese
C. Food additives
D. egg

Q.5) Omalizumab is
E. Anti IgA antibody
F. Fully human anti IgE antibody
G. Humanized anti IgE antibody
H. Third generation antihistamine
 Photo Quiz

Q. Identify the Condition.

 Photo Quiz

Q. Identify the type of urticaria?

Thank You!